Supporting Information

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1 Supporting Information Wiley-VCH Weinheim, Germany Enantioselective Synthesis of a-secondary and a-tertiary Piperazin-2- ones and Piperazines by Catalytic Asymmetric Allylic Alkylation** Katerina M. Korch, Christian Eidamshaus, Douglas C. Behenna, Sangkil Nam, David Horne, and Brian M. Stoltz* anie_ _sm_miscellaneous_information.pdf

2 SI 1 Supporting Information Table of Contents: Materials and thods Representative Procedure 1 for the Preparation of 3-xopiperazine-2- carboxylates and 1,4-Diazepane-2-carboxylates Representative Procedure 2 for the Preparation of 3-xopiperazine-2- carboxylates Procedure for the Preparation of Allyl 4-benzoyl-2-methyl-3-oxo-1- phenylpiperazine-2-carboxylate (8p) Procedure for the Preparation of Allyl 4-benzoyl-1,2-dimethyl-3- oxopiperazine-2-carboxylate (8q) Procedure for the Preparation of 2-Substituted allyl 4-benzoyl-1-benzyl-3- oxopiperazine-2-carboxylates Representative Procedure for the Asymmetric Decarboxylative Allylic Alkylation of 3-xopiperazine-2-carboxylates, 1,4-Diazepane-2- carboxylates, 1-xooctahydro-9aH-pyrido[1,2-a]pyrazine-9acarboxylates, and 3-xo-1,4-diazaspiro[4.5]decane-2-carboxylates Procedures for Preparation of α-quaternary Piperazines Procedures for Deprotection and Functionalization of α-quaternary Piperazin-2-ones Procedures for Preparation of Imatinib Analogs Procedures for the Cell Viability Assay References Determination of Enantiomeric Excess 1 H NMR, 13 C NMR spectra

3 Supporting Information for Stoltz, et al. SI 2 Materials and thods. Unless otherwise stated, reactions were performed in flamedried glassware under an inert atmosphere of argon or nitrogen using dry, deoxygenated solvents. Reaction progress was monitored by thin-layer chromatography (TLC). THF, Et 2, and CH 2 Cl 2 were dried by passage through an activated alumina column under argon. Triethylamine and diisopropylamine were distilled over CaH 2 prior to use. Brine solutions are saturated aqueous solutions of sodium chloride. Allyl Mander s reagents were prepared according to the method of Weber.[1] Allyl 1H-imidazole-1-carboxylate reagents were prepared according to the method of Trost.[2] Phosphinooxazoline (PHX) ligands were prepared by methods described in our previous work.[3] Tris(4,4 - methoxydibenzylideneacetone)dipalladium(0) [Pd 2 (pmdba) 3 ] was prepared according to the method of Ibers[4]or Fairlamb.[5] All other reagents were purchased from Sigma- Aldrich, Acros rganics, Strem, or Alfa Aesar and used as received unless otherwise stated. Reaction temperatures were controlled by an IKAmag temperature modulator unless otherwise indicated. Stirring was accomplished with Teflon coated magnetic stir bars. Glove box manipulations were performed under a N 2 atmosphere. TLC was performed using E. rck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching or KMn 4 staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size mm) was used for flash column chromatography. 1 H NMR spectra were recorded on a Varian Inova 500 MHz spectrometer or Varian rcury 300 MHz spectrometer and are reported relative to residual CHCl 3 (δ 7.26 ppm). 13 C NMR spectra were recorded on a Varian Inova 500 MHz (126 MHz) or Varian rcury 300 MHz (75 MHz) spectrometer and are reported relative to CHCl 3 (δ ppm). Data for 1 H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, h = heptet, m = multiplet, br s = broad singlet, br d = broad doublet, app = apparent. Data for 13C are reported in terms of chemical shifts (δ ppm). IR spectra were obtained using a Perkin Elmer Spectrum BXII spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm 1 ). ptical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm) using a 100 mm path-length cell and are reported as: [α] T D (concentration in g/100 ml, solvent, ee). High-resolution

4 Supporting Information for Stoltz, et al. SI 3 mass spectra (HRMS) were obtained on an Agilent 6200 Series TF with an Agilent G1978A Multimode source in electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), or mixed (MM: ESI-APCI) ionization mode. Syringe pump additions were performed using a KDS 100 syringe pump from KD Scientific. Preparative HPLC was accomplished using an Agilent 1200 Series HPLC with an Agilent Prep-SIL 30 x 250 mm column. Stereochemistry is assigned by analogy to previous results.[6] Representative Procedure 1 for the Preparation of 3-xopiperazine-2- carboxylates and 1,4-Diazepane-2-carboxylates Et Br SI1 1. ethylene diamine EtH 2. NaEt EtH 90 C, 14 h HN NH SI2 BnBr, NEt 3 THF 23 C, 16 h HN SI3 1. LDA, THF -78 C, 1.5 h 2. BzCl 78 C, 4 h 1. LDA, THF -78 C, 1.5 h 2. allyl cyanoformate 78 C, 4 h I, Cs 2 C 3 DMF 23 C, 5 h SI4 10a 8b Piperazin-2-one (SI2) HN NH To a solution of ethylene diamine (3.34 ml, 50.0 mmol) in EtH (39 ml) at 0 C was added ethyl bromoacetate (SI1, 2.76 ml, 25.0 mol) dropwise. The solution was warmed to 23 ºC and allowed to stir overnight open to the air. The resulting white solid was removed by filtration, and the filtrate was transferred to a flame dried flask containing sodium ethoxide (3.74 g, 55.0 mmol) under a nitrogen atmosphere. The solution was then heated to 80 C and allowed to stir for 16 hours under nitrogen atmosphere. The solution was cooled to room temperature and concentrated. Ketopiperazine (SI2) was

5 Supporting Information for Stoltz, et al. SI 4 isolated by flash column chromatography (Si 2, 20% H in CH 2 Cl 2 to 25% H in CH 2 Cl 2 ) as a yellow solid. 64% yield. Product identity was confirmed by comparison to previously reported characterization data. 4-Benzylpiperazin-2-one (SI3) HN A 25 ml round bottom flask was charged with piperazin-2-one (SI2, 3.56 g, 36.3 mmol), triethylamine (8.1 ml, 58.1 mmol), benzyl bromide (3.88 ml, 32.7 mmol), and THF (360 ml) and allowed to stir for 16 hours at 23 ºC. The reaction mixture was then concentrated and taken up in a saturated aqueous NaHC 3 solution. The aqueous solution was extracted with EtAc (5 x 50 ml) and the organic layers were concentrated to approximately 30 ml at which point SI3 precipitated from the solution. The solid was collected by filtration and dried. 62% yield. Product identity was confirmed by comparison to previously reported characterization data. 1-Benzoyl-4-benzylpiperazin-2-one (SI4) Benzyl-protected ketopiperazine (SI3, 1.00 g, 5.26 mmol) was dissolved in 20 ml of THF warmed to 60 ºC and added by cannula to a freshly prepared solution of LDA (6.31 mmol, prepared by the addition of 2.53 ml of 2.5 M nbuli solution to a solution of 1.11 ml of diisopropyl amine in 33 ml THF at 0 C) cooled to 78 C. The reaction mixture was allowed to stir at 78 C for 1.5 hours at which point benzoyl chloride (0.79 ml, 8.84 mmol) was added dropwise. The reaction was stirred at 78 C for another 4 hours at which point full conversion of the starting material was observed by TLC analysis. The reaction mixture was warmed to 23 ºC and poured into 20 ml of H 2 and extracted with EtAc (4 x 20 ml). The organics were combined, washed once with brine, dried

6 Supporting Information for Stoltz, et al. SI 5 with MgS 4, and concentrated under reduced pressure. Ketopiperazine SI4 was isolated by flash column chromatography (Si 2, 20% EtAc in hexanes to 25% EtAc in hexanes) as a pale yellow solid. 83% yield. R f = 0.5 (35% EtAc in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ 7.56 (dd, J = 8.3, 1.3 Hz, 2H), (m, 1H), (m, 7H), (m, 2H), 3.64 (s, 2H), 3.31 (s, 2H), (m, 2H); 13 C NMR (126 MHz, CDCl 3 ) δ 173.8, 169.4, 136.5, 135.9, 131.9, 129.2, 128.7, 128.2, 128.1, 127.9, 61.8, 58.9, 49.3, 45.2; IR (Neat Film, NaCl) 3062, 3027, 2958, 2903, 2809, 1708, 1683, 1600, 1491, 1450, 1401, 1362, 1282, 1237, 1197, 1162, 1136, 1073, 950, 885, 795, 730 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 18 H 19 N 2 2 [M+H] + : , found Allyl 4-benzoyl-1-benzyl-3-oxopiperazine-2-carboxylate (10a) Ketopiperazine (SI4, 1.40 g, 4.76 mmol) was dissolved in 25 ml of dry THF and added via cannula to a freshly prepared solution of LDA (5.71 mmol) in 23 ml dry THF at 78 C. The resulting dark red solution was allowed to stir at 78 C for one hour at which point allyl cyanoformate (58.1 mg, 5.23 mmol) was added neat. After 2.5 hours, the reaction reached completion according to TLC analysis. The reaction mixture was warmed to 23 ºC and poured into 20 ml of H 2 and then extracted with EtAc (4 x 20 ml). The combined organics were washed once with brine, dried with MgS 4, and concentrated under reduced pressure. Ketopiperazine 10a was isolated by flash column chromatography (Si 2, 10% EtAc in hexanes) as a white solid. 63% yield. R f = 0.4 (20% EtAc in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ 7.64 (dd, J = 8.3, 1.2 Hz, 2H), (m, 1H), (m, 5H), 7.31 (td, J = 8.6, 8.1, 3.9 Hz, 2H) (m, 1H), 5.40 (dd, J = 17.2, 1.4 Hz, 1H), 5.31 (dd, J = 10.4, 1.1 Hz, 1H), 4.73 (d, J = 6.0 Hz, 2H), 4.17 (s, 1H), 3.93 (ddd, J = 12.5, 8.1, 4.3 Hz, 1H), 3.84 (d, J = 13.4 Hz, 1H), (m, 2H), 3.32 (ddd, J = 12.2, 8.1, 3.9 Hz, 1H), 2.80 (dt, J = 12.4, 5.0 Hz, 1H); 13 C NMR (126 MHz, CDCl 3 ) δ 173.7, 167.7, 166.6, 136.5, 135.2, 132.2, 131.4, 129.1, 128.7, 128.4, 128.3, 128.0, 119.7, 69.7, 66.6, 58.8, 45.0, 44.9; IR (Neat Film, NaCl)

7 Supporting Information for Stoltz, et al. SI , 3029, 2846, 1733, 1690, 1600, 1583, 1494, 1450, 1368, 1281, 1232, 1154, 1091, 1074, 985, 948, 945, 795, 731 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 22 H 23 N 2 4 [M+H] + : , found Allyl 4-benzoyl-1-benzyl-2-methyl-3-oxopiperazine-2-carboxylate (8b) Ketopiperazine (10a, mg, 1.32 mmol) was dissolved in 8.8 ml of dry DMF along with Cs 2 C 3 (0.75 g, 2.31 mmol) and methyl iodide (90.0 µl, 1.45 mmol) and allowed to stir for 10.5 hours at 23 ºC. The solution was then poured into 10 ml of H 2 and extracted with EtAc (4 x 10 ml). The combined organics were washed once with brine, dried with MgS 4, and concentrated under reduced pressure. Acylated ketopiperazine 8b was isolated by flash column chromatography (Si 2, 15% EtAc in hexanes to 20% EtAc in hexanes) as a white solid. 35% yield. R f = 0.4 (20% EtAc in hexanes); 1 H NMR (300 MHz, CDCl 3 ) δ (m, 2H), (m, 1H), (m, 6H), (m, 1H), 6.01 (ddt, J = 17.1, 10.4, 6.0 Hz, 1H), (m, 1H), 5.34 (dq, J = 10.4, 1.1 Hz, 1H), 4.77 (dt, J = 6.0, 1.3 Hz, 2H), 4.01 (d, J = 14.0 Hz, 1H), (m, 2H), 3.43 (d, J = 14.0 Hz, 1H), 3.15 (ddd, J = 13.4, 9.3, 4.2 Hz, 1H), 2.90 (dt, J = 12.6, 4.2 Hz, 1H), 1.78 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 173.9, 170.0, 169.3, 137.9, 135.5, 132.0, 131.5, 128.7, 128.6, 128.3, 128.2, 127.8, 119.9, 71.4, 66.6, 54.8, 44.9, 43.0, 20.2; IR (Neat Film, NaCl) 3062, 2943, 2848, 1741, 1685, 1600, 1495, 1449, 1400, 1379, 1315, 1284, 1235, 1150, 1109, 928, 795, 723 cm 1 ; HRMS (MM: ESI- APCI or EI+) m/z calc'd for C 23 H 25 N 2 4 [M+H] + : , found Allyl 1,4-dibenzoyl-2-methyl-3-oxopiperazine-2-carboxylate (8a) NBz

8 Supporting Information for Stoltz, et al. SI 7 Ketopiperazine 8a was prepared according to representative procedure 1, employing benzoyl chloride instead of benzyl bromide, and was isolated by flash column chromatography (Si 2, 15% EtAc in hexanes to 25% EtAc in hexanes) as a colorless solid. R f = 0.3 (20% EtAc in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), (m, 4H), 7.41 (ddt, J = 7.8, 6.5, 1.0 Hz, 2H), 5.98 (ddt, J = 17.2, 10.4, 5.8 Hz, 1H), 5.39 (dq, J = 17.2, 1.5 Hz, 1H), 5.28 (dq, J = 10.4, 1.2 Hz, 1H), (m, 2H), (m, 2H), 4.00 (ddd, J = 14.1, 5.2, 3.6 Hz, 1H), (m, 1H), 1.99 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 172.3, 170.2, 169.1, 167.3, 134.7, 134.6, 132.4, 131.7, 130.8, 129.0, 128.5, 127.9, 127.0, 119.0, 69.2, 67.2, 44.6, 44.3, 19.6; IR (Neat Film, NaCl) 3583, 2943, 1762, 1700, 1690, 1647, 1600, 1448, 1405, 1370, 1284, 1255, 1209, 1149, 1123, 991, 942, 789, 725 cm 1 ; HRMS (MM: ESI- APCI or EI+) m/z calc'd for C 23 H 23 N 2 5 [M+H] + : , found Allyl 4-benzoyl-1-(4-methoxybenzyl)-2-methyl-3-oxopiperazine-2-carboxylate (8c) NPMB Ketopiperazine 8c was prepared according to representative procedure 1 employing 4- methoxybenzyl chloride instead of benzyl bromide, and was isolated by flash column chromatography (Si 2, 10% EtAc in hexanes to 20% EtAc in hexanes) as a yellow oil. R f = 0.4 (20% EtAc in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), (m, 1H), (m, 2H), (m, 2H), (m, 2H), 6.01 (ddt, J = 16.4, 10.4, 6.0 Hz, 1H), 5.43 (dq, J = 17.2, 1.4 Hz, 1H), 5.34 (dq, J = 10.4, 1.1 Hz, 1H), (m, 2H), 3.90 (d, J = 13.7 Hz, 1H), 3.82 (s, 3H), 3.80 (t, J = 4.0 Hz, 1H), 3.70 (ddd, J = 12.5, 9.8, 4.2 Hz, 1H), 3.32 (d, J = 13.7 Hz, 1H), 3.10 (ddd, J = 13.2, 9.8, 3.7 Hz, 1H), 2.87 (dt, J = 12.6, 4.2 Hz, 1H), 1.75 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 174.0, 170.4, 169.4, 159.2, 135.6, 132.0, 131.6, 130.2, 129.6, 128.2, 128.1, 119.8, 114.0, 71.4, 66.5, 55.4, 54.1, 45.2, 42.7, 20.1; IR (Neat Film, NaCl) 3062, 2997, 2949, 2836, 1742, 1687, 1611, 1512, 1465, 1449, 1378, 1285, 1245, 1171, 1150, 1108, 1034, 926, 825

9 Supporting Information for Stoltz, et al. SI 8 cm 1 ; HRMS (MM: ESI-APCI or EI+) m/z calc'd for C 24 H 27 N 2 5 [M+H] + : , found Allyl 1-benzyl-4-(4-fluorobenzoyl)-2-methyl-3-oxopiperazine-2-carboxylate (8d) F N Ketopiperazine 8d was prepared according to representative procedure 1 employing 4- fluoro-benzoyl chloride instead of benzoyl chloride, and was isolated by flash column chromatography (Si 2, 15% EtAc in hexanes) as a colorless solid. R f = 0.5 (20% EtAc in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), 7.35 (d, J = 4.4 Hz, 4H), (m, 1H), (m, 2H), 6.01 (ddt, J = 17.1, 10.4, 6.0 Hz, 1H), 5.44 (dd, J = 17.2, 1.4 Hz, 1H), 5.36 (dd, J = 10.4, 1.1 Hz, 1H), (m, 2H), 4.00 (d, J = 14.0 Hz, 1H), (m, 2H), 3.39 (d, J = 14.0 Hz, 1H), 3.10 (ddd, J = 13.5, 9.6, 4.1 Hz, 1H), 2.88 (dt, J = 12.7, 4.1 Hz, 1H), 1.75 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 172.9, 170.4, 169.4, (d, 1 J CF = Hz), 138.3, (d, 4 J CF = 3.3 Hz), (d, 3 J CF = 9.1 Hz), 128.7, 128.4, 127.7, 119.9, (d, 2 J CF = 22.2 Hz), 71.4, 66.5, 54.7, 45.3, 43.0, 20.2; IR (Neat Film, NaCl) 3064, 3028, 3001, 2947, 2902, 2844, 1742, 1689, 1601, 1509, 1454, 1409, 1379, 1316, 1283, 1235, 1150, 1110, 996, 928, 849, 765 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 23 H 24 FN 2 4 [M+H] + : , found Allyl 1-benzyl-4-(4-methoxybenzoyl)-2-methyl-3-oxopiperazine-2-carboxylate (8e) N Ketopiperazine 8e was prepared according to representative procedure 1 employing 4- methoxy-benzoyl chloride instead of benzoyl chloride, and was isolated by flash column chromatography (Si 2, 20% EtAc in hexanes) as a white solid. R f = 0.4 (30% EtAc

10 Supporting Information for Stoltz, et al. SI 9 in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), (m, 4H), 7.29 (ddt, J = 8.6, 5.5, 2.9 Hz, 1H), (m, 2H), 6.02 (ddt, J = 16.4, 10.4, 6.0 Hz, 1H), 5.44 (dq, J = 17.2, 1.3 Hz, 1H), 5.34 (dd, J = 10.4, 1.1 Hz, 1H), 4.77 (dt, J = 5.9, 1.2 Hz, 2H), 3.98 (d, J = 14.0 Hz, 1H), 3.85 (s, 3H), (m, 2H), 3.38 (d, J = 14.0 Hz, 1H), 3.11 (ddd, J = 13.2, 8.4, 5.0 Hz, 1H), 2.87 (dt, J = 12.6, 4.1 Hz, 1H), 1.76 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 173.4, 170.1, 169.6, 163.1, 138.4, 131.7, 131.0, 128.7, 128.4, 127.6, 127.4, 119.8, 113.6, 71.3, 66.5, 55.5, 54.8, 45.3, 43.0, 20.2; IR (Neat Film, NaCl) 3583, 2917, 2848, 1740, 1679, 1602, 1511, 1458, 1315, 1256, 1170, 1149, 1109, 1026, 927, 843, 739 cm -1 ; HRMS (MM: ESI-APCI) m/z calc d for C 24 H 27 N 2 5 [M+H] + : , found Allyl 1-benzyl-4-(2-fluorobenzoyl)-2-methyl-3-oxopiperazine-2-carboxylate (8f) F N Ketopiperazine 8f was prepared according to representative procedure 1 employing 2- fluoro-benzoyl chloride instead of benzoyl chloride, and was isolated by flash column chromatography (Si 2, 20% EtAc in hexanes) as a yellow oil. R f = 0.4 (20% EtAc in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ 7.49 (td, J = 7.4, 1.7 Hz, 1H), 7.43 (dddd, J = 8.3, 7.2, 5.2, 1.8 Hz, 1H), (m, 4H), (m, 1H), 7.20 (td, J = 7.6, 1.0 Hz, 1H), 7.04 (ddd, J = 10.1, 8.3, 0.8 Hz, 1H), (m, 1H), 5.37 (dq, J = 17.2, 1.4 Hz, 1H), 5.28 (dq, J = 10.4, 1.1 Hz, 1H), (m, 2H), 3.99 (dt, J = 12.6, 4.0 Hz, 1H), 3.89 (d, J = 14.0 Hz, 1H), 3.67 (ddd, J = 12.7, 9.5, 4.3 Hz, 1H), 3.37 (d, J = 14.0 Hz, 1H), 3.14 (ddd, J = 13.0, 9.5, 3.7 Hz, 1H), 2.86 (dt, J = 12.7, 4.4 Hz, 1H), 1.75 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 170.7, 169.4, 168.6, (d, 1 J CF = Hz), 138.2, (d, 4 J CF = 8.5 Hz), 131.7, 129.5, 128.7, 128.5, 127.7, (d, 3 J CF = 14.6 Hz), (d, 5 J CF = 3.4 Hz), 119.5, (d, 2 J CF = 21.6 Hz), 71.8, 66.5, 54.5, 44.7, 42.5, 20.3; IR (Neat Film, NaCl) 3066, 3029, 2944, 2847, 1743, 1690, 1614, 1491, 1453, 1379, 1301, 1230, 1146, 928, 755 cm -1 ; HRMS (MM: ESI-APCI) m/z calc d for C 23 H 24 FN 2 4 [M+H] + : , found

11 Supporting Information for Stoltz, et al. SI 10 3-Allyl 1-benzyl 4-benzyl-3-methyl-2-oxopiperazine-1,3-dicarboxylate (8g) Bn N Ketopiperazine 8g was prepared according to representative procedure 1 employing benzyl chloroformate instead of benzoyl chloride, and was isolated by flash column chromatography (Si 2, 10% EtAc in hexanes to 20% EtAc in hexanes) as a yellow oil. R f = 0.5 (20% EtAc in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), (m, 5H), (m, 1H), 5.86 (ddt, J = 17.1, 10.5, 5.8 Hz, 1H), 5.30 (dq, J = 17.2, 1.5 Hz, 1H), 5.22 (d, J = 2.6 Hz, 2H), 5.18 (dq, J = 10.4, 1.2 Hz, 1H), (m, 2H), 3.78 (d, J = 14.0 Hz, 1H), 3.70 (dt, J = 12.2, 3.9 Hz, 1H), (m, 1H), 3.23 (d, J = 14.0 Hz, 1H), 2.97 (ddd, J = 13.1, 9.7, 3.7 Hz, 1H), 2.65 (dt, J = 12.7, 4.3 Hz, 1H), 1.68 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 169.5, 168.9, 153.6, 138.2, 135.3, 131.7, 128.7, 128.6, 128.5, 128.4, 128.2, 127.6, 119.2, 72.2, 68.9, 66.2, 54.4, 46.2, 42.5, 20.9; IR (Neat Film, NaCl) 2944, 2848, 1779, 1723, 1495, 1456, 1378, 1315, 1283, 1213, 1112, 1021, 995, 781, 739 cm -1 ; HRMS (MM: ESI-APCI) m/z calc d for C 24 H 27 N 2 5 [M+H] + : , found Allyl 4-benzoyl-1-benzyl-2-ethyl-3-oxopiperazine-2-carboxylate (8h) Et Ketopiperazine 8h was prepared according to representative procedure 1 employing ethyl iodide instead of methyl iodide, and was isolated by flash column chromatography (Si 2, 10% EtAc in hexanes to 20% EtAc in hexanes) as a yellow oil. R f = 0.6 (20% EtAc in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), (m, 1H), (m, 6H), (m, 1H), 6.04 (ddt, J = 17.1, 10.4, 6.0 Hz, 1H), 5.46 (dq, J = 17.2, 1.4 Hz, 1H), 5.37 (dq, J = 10.4, 1.1 Hz, 1H), (m, 2H), 4.08 (d, J = 14.0 Hz, 1H), 3.83 (dt, J = 12.6, 2.8 Hz, 1H), 3.69 (td, J = 12.2, 3.8 Hz, 1H), 3.29 (d, J = 14.0

12 Supporting Information for Stoltz, et al. SI 11 Hz, 1H), 3.17 (td, J = 12.1, 3.1 Hz, 1H), 2.95 (ddd, J = 12.4, 3.6, 2.5 Hz, 1H), 2.30 (dq, J = 14.6, 7.3 Hz, 1H), 2.15 (dq, J = 14.7, 7.4 Hz, 1H), 1.04 (t, J = 7.3 Hz, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 174.1, 169.2, 169.0, 138.2, 135.7, 132.1, 131.7, 128.8, 128.4, 128.3, 128.2, 127.6, 119.9, 75.0, 66.3, 54.5, 44.9, 43.0, 26.1, 8.4; IR (Neat Film, NaCl) 3063, 3030, 2960, 2839, 1744, 1683, 1600, 1495, 1451, 1400, 1377, 1321, 1284, 1225, 1151, 1119, 1082, 987, 962, 940, 796, 738, 720 cm -1 ; HRMS (MM: ESI-APCI) m/z calc d for C 24 H 27 N 2 4 [M+H] + : , found Phenylallyl 4-benzoyl-1-benzyl-2-methyl-3-oxopiperazine-2-carboxylate (8l) Ph Ketopiperazine 8l was prepared according to representative procedure 1 starting from 10d instead of 10a, and was isolated by flash column chromatography (Si 2, 15% EtAc in hexaes) as a yellow oil. R f = 0.4 (15% EtAc in hexanes) 1 H NMR (500 MHz, CDCl 3 ) δ 7.63 (dd, J = 8.2, 1.2 Hz, 2H), (m, 3H), (m, 4H), (m, 3H), (m, 1H), 7.23 (d, J = 6.9 Hz, 2H), 5.63 (s, 1H), (m, 1H), 5.32 (dd, J = 12.9, 0.9 Hz, 1H), (m, 1H), 3.87 (d, J = 14.0 Hz, 1H), (m, 2H), 3.12 (d, J = 14.0 Hz, 1H), 2.82 (ddd, J = 13.8, 9.5, 4.5 Hz, 1H), 2.67 (dt, J = 12.7, 3.9 Hz, 1H), 1.72 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 173.9, 170.2, 169.5, 142.5, 138.3, 138.0, 135.6, 131.9, 128.8, 128.6, 128.5, 128.3, 128.2, 128.1, 127.5, 126.4, 117.2, 71.3, 67.3, 54.4, 45.1, 42.6, 20.6; IR (Neat Film, NaCl) 3060, 3029, 3001, 2944, 2900, 2845, 1741, 1686, 1600, 1495, 1466, 1449, 1400, 1379, 1316, 1284, 1236, 1150, 1107, 1028, 918, 780, 723 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 29 H 29 N 2 4 [M+H] + : , found

13 Supporting Information for Stoltz, et al. SI 12 2-Chloroallyl 4-benzoyl-1-benzyl-2-methyl-3-oxopiperazine-2-carboxylate (8m) Cl Ketopiperazine 8m was prepared according to representative procedure 1 starting from 10c instead of 10a, and was isolated by flash column chromatography (Si 2, 5% EtAc in hexanes to 10% EtAc in hexanes) as a yellow oil. R f = 0.4 (15% EtAc in hexanes) 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), (m, 1H), (m, 2H), (m, 4H), (m, 1H), 5.59 (dt, J = 1.9, 1.0 Hz, 1H), 5.51 (d, J = 1.9 Hz, 1H), 4.88 (d, J = 14.0 Hz, 1H), 4.80 (d, J = 13.3 Hz, 1H), 4.00 (d, J = 14.0 Hz, 1H), 3.86 (dt, J = 12.4, 3.8 Hz, 1H), 3.73 (ddd, J = 12.4, 10.0, 4.1 Hz, 1H), 3.45 (d, J = 14.0 Hz, 1H), 3.19 (ddd, J = 13.5, 10.0, 3.6 Hz, 1H), 2.91 (dt, J = 12.7, 4.1 Hz, 1H), 1.79 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 173.9, 170.1, 169.1, 138.3, 135.7, 135.4, 132.0, 128.7, 128.5, 128.3, 128.2, 127.7, 116.9, 71.6, 67.4, 54.7, 45.2, 43.0, 20.5; IR (Neat Film, NaCl) 3062, 3029, 2946, 2846, 1746, 1686, 1639, 1600, 1495, 1450, 1401, 1379, 1316, 1283, 1234, 1177, 1150, 1105, 1027, 1000, 971, 912, 724 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 23 H 24 N 2 4 Cl [M+H] + : , found Allyl 4-benzoyl-1-benzyl-2-methyl-3-oxo-1,4-diazepane-2-carboxylate (8o) 1,4-Diazepane 8o was prepared according to representative procedure 1 employing 1,3- diaminopropane instead of ethylene diamine, and was isolated by flash column chromatography (Si 2, 10% EtAc in hexanes to 20% EtAc in hexanes) as a colorless solid. R f = 0.7 (20% EtAc in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ 7.65 (m, 2H), (m, 1H), (m, 5H), 7.28 (m, 2H), 6.00 (ddt, J = 17.2, 10.4, 6.0 Hz, 1H), 5.44 (dd, J = 17.2, 1.4 Hz, 1H), 5.33 (dd, J = 10.4, 1.4 Hz, 1H), (m, 2H), 4.29 (ddd, J = 14.4, 8.8, 3.0 Hz, 1H), 3.92 (ddd, J = 14.4, 6.1, 3.0 Hz, 1H), 3.77 (d, J =

14 Supporting Information for Stoltz, et al. SI Hz, 1H), 3.68 (d, J = 14.2 Hz, 1H), 3.44 (ddd, J = 15.4, 10.9, 4.9 Hz, 1H), 2.89 (ddd, J = 15.4, 6.1, 3.0 Hz, 1H), 1.79 (s, 3H), (m, 1H), (m, 1H); 13 C NMR (126 MHz, CDCl 3 ) δ 174.8, 173.7, 170.4, 139.3, 136.2, 131.9, 131.6, 128.6, 128.4, 128.3, 128.1, 127.4, 119.8, 75.1, 66.5, 53.1, 46.8, 42.9, 26.9, 22.7; IR (Neat Film, NaCl) 3062, 3028, 2945, 1742, 1682, 1600, 1494, 1450, 1377, 1357, 1281, 1256, 1139, 1104, 1024, 947, 793, 740, 724 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 24 H 27 N 2 4 [M+H] + : , found Representative Procedure 2 for the Preparation of 3-oxopiperazine-2- carboxylates H NH 2 SI5 N SI8 SI10 SCl 2 EtH 90 C, 4 h H Et HCl NH 2 SI6 1. Tf 2, CH 2 Cl 2 0 C, 10 min 2. 2,6-lutidine 0 C, 10 min 3. SI7, NEt 3 0 C 23 C, 14 h 4. N 2 H 4 H 2 H 23 C, 16 h 1. benzaldehyde NEt 3, H 23 C, 10 h HN 1.KHMDS, THF then slow addition of SI7 78 C, 1.5 h 2. allyl cyanoformate 78 C, 4 h 2. NaBH 4 0 C, 2 h SI9 Et NHBn SI7 1. LDA, THF 78 C, 1.5 h 2. BzCl 78 C, 4 h 8b N-Benzylalanine ethyl ester (SI7) Et NHBn D,L-Alanine (SI5, 1.50 g, 16.8 mmol) was dissolved in EtH (100 ml) and cooled to 0 C. Thionyl chloride (3.67 ml, 50.5 mmol) was then added dropwise and the resulting solution was heated to reflux for 5 hours. The reaction mixture was then cooled to 23 ºC and excess thionyl chloride and ethanol were removed by rotary evaporation to yield

15 Supporting Information for Stoltz, et al. SI 14 alanine ethyl ester hydrogen chloride salt (SI6) which was used in the following step without further purification. Alanine ester hydrogen chloride salt (SI6) was dissolved in H (17 ml). Then triethylamine (2.6 ml, 18.8 mmol) was added and the solution was allowed to stir for 15 minutes at which point benzaldehyde (1.74 ml, 17.1 mmol) was added neat. The resulting solution was allowed to stir for 10 hours open to air. Then the solution was cooled to 0 C and NaBH 4 (1.29 g, 34.1 mmol) was added portionwise. The mixture was allowed to stir overnight. The reaction mixture was then carefully poured into 25 ml of 2 N HCl and was washed with Et 2 (1 x 20 ml). The aqueous layer was then basified with 2 N NaH and was extracted with CH 2 Cl 2 (4 x 40 ml). The organic layers were combined and washed once with brine, dried with MgS 4, and concentrated under reduced pressure to give N-benzylalanine ethyl ester (SI7) in a 90% yield from alanine (SI5). Product identity was confirmed by comparison to previously reported characterization data. 4-Benzyl-3-methylpiperazin-2-one (SI9) HN A solution of N-(2-hydroxyethyl)phthalimide (SI8, 769 mg, 4.00 mmol) in CH 2 Cl 2 (4 ml) under argon atmosphere was cooled to 0 C. Triflic anhydride (0.81 ml, 4.82 mmol) was added dropwise, and the resulting solution was allowed to stir for 10 minutes at 0 C. Then 2,6-lutidine (560 µl, 4.82 mmol) was added and allowed to stir for another 10 minutes before triethylamine (670 µl, 4.82 mmol) and SI7 (suspended in 4 ml of CH 2 Cl 2 ) were added sequentially in dropwise fashion. The solution was warmed to 23 ºC and allowed to stir overnight under Ar atmosphere. The reaction mixture was diluted with additional CH 2 Cl 2 and washed with 10% aqueous citric acid (2 x 10 ml). The organics were dried with Na 2 S 4 and concentrated. The resulting oil was taken up in H (22 ml), hydrazine hydrate (0.45 ml, 9.20 mmol) was added, and the mixture was allowed to stir overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Ketopiperazine SI9 was isolated by flash column

16 Supporting Information for Stoltz, et al. SI 15 chromatography (Si 2, 3% H in CH 2 Cl 2 to 5% H in CH 2 Cl 2 ) as a yellow solid. 54% yield. R f = 0.5 (10% H in CH 2 Cl 2 ); 1 H NMR (500 MHz, CDCl 3 ) δ (m, 5H), 6.02 (br s, 1H), 3.94 (d, J = 13.5 Hz, 1H), 3.42 (d, J = 13.5 Hz, 1H), (m, 3H), 2.91 (dt, J = 12.3, 4.8 Hz, 1H), 2.48 (ddd, J = 12.3, 7.4, 4.5 Hz, 1H), 1.48 (d, J = 6.9 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 173.0, 138.2, 128.9, 128.5, 127.4, 60.3, 58.3, 45.3, 41.2, 15.5; IR (Neat Film, NaCl) 3203, 3057, 2983, 2953, 2923, 2878, 2819, 1667, 1495, 1451, 1345, 1303, 1147, 1088, 1072, 1051, 1024, 890, 822, 750 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 12 H 17 N 2 [M+H] + : , found Benzoyl-4-benzyl-3-methylpiperazin-2-one (SI10) Ketopiperazine (SI9, 24.7 mg, 1.21 mmol) was dissolved in 6 ml of dry THF and added by cannula to a freshly prepared solution of LDA (1.45 mmol) in 6.1 ml dry THF at 78 C. The reaction mixture was allowed to stir at 78 C for 1.5 hours at which point benzoyl chloride (0.18 ml, 1.57 mmol) was added dropwise. The reaction was stirred at 78 C for another 4 hours at which point full conversion of the starting material was observed by TLC analysis. The reaction mixture was warmed to room temperature and poured into 15 ml of H 2 and extracted with EtAc (4 x 20 ml). The organics were combined and washed once with brine, dried with Na 2 S 4, and concentrated under reduced pressure. Ketopiperazine SI10 was isolated by flash column chromatography (Si 2, 10% EtAc in hexanes to 15% EtAc in hexanes) as a colorless solid. 81% yield. R f = 0.5 (30% EtAc in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ 7.54 (app d, J = 7.3 Hz, 2H), (m, 1H), (m, 6H), (m, 1H), 3.99 (d, J = 13.5 Hz, 1H), (m, 1H), (m, 1H), 3.46 (d, J = 13.5 Hz, 1H), 3.37 (app q, J = 6.1 Hz, 1H), (m, 1H), (m, 1H), 1.55 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 173.9, 173.5, 136.0, 131.8, 129.9, 129.0, 128.7, 128.3, 128.0, 127.7, 62.3, 58.3, 46.0, 44.7, 15.7; IR (Neat Film, NaCl) 3085, 3062, 3029, 2979, 2942, 2898, 2814, 1693, 1600, 1583, 1455, 1367, 1286, 1228, 1145, 1096, 1075, 1027, 978, 945, 896, 872, 795,

17 Supporting Information for Stoltz, et al. SI cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 19 H 21 N 2 2 [M+H] + : , found Allyl 4-benzoyl-1-benzyl-2-methyl-3-oxopiperazine-2-carboxylate (8b) To a cooled solution of KHMDS (64.0 g, 3.19 mmol) in THF (20 ml) at 78 ºC was added a solution of ketopiperazine (SI10, 89.0 g, 2.90 mmol) in THF (10 ml) over a period of 6.5 hours by syringe pump. The resulting solution was allowed to stir for an additional 30 minutes at which point allyl cyanoformate (39.0 g, 3.48 mmol) was added neat. The reaction mixture was stirred at 78 C for 2 hours at which point full conversion of the starting material was observed by TLC analysis. The reaction mixture was warmed to 23 ºC, poured into 15 ml of H 2, and extracted with EtAc (4 x 20 ml). The organics were combined, washed once with brine, dried with Na 2 S 4, and concentrated under reduced pressure. Ketopiperazine 8b was isolated by flash column chromatography (Si 2, 15% EtAc in hexanes to 20% EtAc in hexanes) as a light yellow solid. 61% yield. Product identity was confirmed by comparison to characterization data reported above. Allyl 4-benzoyl-1-benzyl-2-isobutyl-3-oxopiperazine-2-carboxylate (8i) Ketopiperazine 8i was prepared according to representative procedure 2 starting from D,L-leucine instead of D,L-alanine, and was isolated by flash column chromatography (Si 2, 10% Et 2 in hexanes to 15% Et 2 in hexanes) as a white solid. R f = 0.4 (20% Et 2 in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), (m, 1H), (m, 6H), (m, 1H), 6.05 (ddt, J = 17.1, 10.4, 6.0 Hz, 1H), 5.46 (dq, J

18 Supporting Information for Stoltz, et al. SI 17 = 17.1, 1.4 Hz, 1H), 5.38 (dq, J = 10.4, 1.4 Hz, 1H), (m, 2H), 4.11 (d, J = 14.0 Hz, 1H), (m, 2H), 3.23 (d, J = 14.0 Hz, 1H), 3.15 (ddd, J = 12.4, 10.1, 5.1 Hz, 1H), 2.95 (dt, J = 12.4, 3.0 Hz, 1H), 2.28 (dd, J = 15.0, 4.3 Hz, 1H), 2.18 (dd, J = 15.0, 9.3 Hz, 1H), 2.04 (ddtd, J = 10.1, 9.3, 6.7, 4.3 Hz, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.86 (d, J = 6.7 Hz, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 174.4, 169.0, 168.8, 137.9, 135.6, 132.1, 131.7, 128.8, 128.5, 128.3, 128.1, 127.6, 120.0, 73.8, 66.4, 54.8, 45.0, 43.0, 40.2, 24.7, 23.8, 22.4; IR (Neat Film, NaCl) 3063, 3030, 2958, 2870, 1739, 1687, 1683, 1601, 1495, 1451, 1368, 1317, 1284, 1227, 1151, 1107, 984, 935, 795, 767, 722 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 26 H 31 N 2 4 [M+H] + : , found Allyl 4-benzoyl-1,2-dibenzyl-3-oxopiperazine-2-carboxylate (8j) Bn Ketopiperazine 8j was prepared according to representative procedure 2 starting from D,L-phenylalanine instead of D,L-alanine, and was isolated by flash column chromatography (Si 2, 15% Et 2 in hexanes) as a white solid. R f = 0.5 (30% Et 2 in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ (m, 3H), (m, 4H), 7.29 (app s, 6H), 7.22 (app d, J = 7.1 Hz, 2H), 6.07 (ddt, J = 17.2, 10.4, 6.0 Hz, 1H), 5.49 (dd, J = 17.2, 1.3 Hz, 1H), 5.39 (dd, J = 10.4, 1.3 Hz, 1H), (m, 2H), 4.29 (d, J = 13.8 Hz, 1H), (m, 1H), 3.61 (d, J = 14.6 Hz, 1H), 3.44 (d, J = 14.6 Hz, 1H), 3.32 (d, J = 13.8 Hz, 1H), (m, 2H), (m, 1H); 13 C NMR (126 MHz, CDCl 3 ) δ 173.6, 168.9, 168.6, 137.3, 135.9, 135.5, 132.1, 131.6, 131.0, 128.7, 128.7, 128.4, 128.3, 128.1, 127.6, 127.1, 120.0, 75.5, 66.6, 54.5, 44.1, 43.1, 38.7; IR (Neat Film, NaCl) 3086, 3062, 3030, 2845, 1738, 1690, 1601, 1495, 1455, 1403, 1373, 1322, 1283, 1242, 1218, 1102, 1029, 942, 860, 794, 771 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 29 H 29 N 2 4 [M+H] + : , found

19 Supporting Information for Stoltz, et al. SI 18 Allyl 4-benzoyl-1-benzyl-2-[(benzyloxy)methyl]-3-oxopiperazine-2-carboxylate (8k) Bn Ketopiperazine 8k was prepared according to representative procedure 2 starting from - (phenylmethyl)-(l)-serine instead of D,L-alanine, and was isolated by flash column chromatography (Si 2, 10% EtAc in hexanes) as a colorless solid. R f = 0.4 (20% EtAc in hexanes) 1 H NMR (500 MHz, CDCl 3 ) δ 7.67 (m, 2H), (m, 1H), (m, 4H), (m, 8H), 5.96 (ddt, J = 17.1, 10.4, 6.0 Hz, 1H), 5.39 (dd, J = 17.1, 1.4 Hz, 1H), (dd, J = 10.4, 1.4 Hz, 1H), (m, 3H), 4.61 (d, J = 12.2 Hz, 1H), 4.20 (d, J = 10.0 Hz, 1H), 4.07 (d, J = 10.0 Hz, 1H), (m, 2H), (m, 1H), 3.50 (d, J = 14.0 Hz, 1H), 3.18 (ddd, J = 12.7, 9.5, 4.2 Hz, 1H), 3.10 (dt, J = 12.2, 4.2 Hz, 1H); 13 C NMR (126 MHz, CDCl 3 ) δ 173.7, 168.7, 168.0, 138.3, 137.9, 135.5, 132.0, 131.5, 128.7, 128.6, 128.4, 128.4, 128.1, 127.9, 127.8, 127.6, 119.8, 74.7, 74.0, 71.4, 66.4, 54.4, 44.7, 43.5; IR (Neat Film, NaCl) 3062, 3027, 2938, 2853, 1738, 1687, 1600, 1495, 1452, 1376, 1321, 1284, 1226, 1148, 1099, 1047, 973, 940, 795, 743 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 30 H 31 N 2 5 [M+H] + : , found Allyl 2-benzoyl-1-oxooctahydro-9aH-pyrido[1,2-a]pyrazine-9a-carboxylate (8n) N NBz Bicycle 8n was prepared according to representative procedure 2 starting from pipecolic acid and omitting the benzyl protection operation, and was isolated by flash column chromatography (Si 2, 15% EtAc and 1% NEt 3 in hexanes) as a white solid. R f = 0.3 (25% EtAc in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), (m, 1H), (m, 2H), 6.00 (ddt, J = 17.1, 10.4, 6.0 Hz, 1H), 5.41 (dd, J = 17.1, 1.4 Hz, 1H), 5.34 (dd, J = 10.4, 1.4 Hz, 1H), 4.76 (dt, J = 6.0, 1.4 Hz, 2H), 4.04 (td, J = 11.9,

20 Supporting Information for Stoltz, et al. SI Hz, 1H), 3.66 (ddd, J = 12.6, 4.7, 2.9 Hz, 1H), 3.49 (ddd, J = 12.9, 11.9, 4.7 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), 1.88 (m, 1H), (m, 4H); 13 C NMR (126 MHz, CDCl 3 ) δ 174.4, 169.9, 169.8, 135.7, 131.9, 131.4, 128.2, 128.1, 120.0, 70.3, 66.4, 50.0, 47.2, 44.4, 31.3, 24.7, 20.6; IR (Neat Film, NaCl) 2940, 2860, 1721, 1683, 1600, 1449, 1382, 1355, 1283, 1244, 1150, 1124, 987, 940, 726 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 19 H 23 N 2 4 [M+H] + : , found Procedure for the Preparation of Allyl 4-benzoyl-2-methyl-3-oxo-1- phenylpiperazine-2-carboxylate (8p) Et Br SI11 aniline K 2 C 3, KI CH 3 CN 85 C, 2 days Et NHPh SI12 N SI8 H 1. Tf 2, CH 2 Cl 2 0 C, 10 min 2. 2,6-lutidine 0 C, 10 min 3. SI12, NEt 3 0 C 23 C, 14 h 4. N 2 H 4 H 2 H 23 C, 16 h 1. LDA, THF 78 C, 1.5 h 2. BzCl 78 C, 4 h 1.KHMDS, THF then slow addition of substrate 78 C, 1.5 h 2. allyl cyanoformate 78 C, 4 h NPh 8p Ethyl phenylalaninate (SI12) Et NHPh Ethyl 2-bromopropionate (SI11, 2 ml, 15.4 mmol) was taken up in acetonitrile (18 ml) along with aniline (1.17 ml, 12.8 mmol), potassium carbonate (3.37 g, 24.4 mmol), and potassium iodide (0.26 g, 0.12 mmol) and heated to reflux for 48 hours. The reaction mixture was filtered and the filtrate concentrated. Ethyl phenylalaninate (SI12) was isolated by flash column chromatography (Si 2, 20% EtAc in hexanes) as a colorless solid. R f = 0.6 (30% EtAc in hexanes). Product identity was confirmed by comparison to previously reported characterization data.

21 Supporting Information for Stoltz, et al. SI 20 Allyl 4-benzoyl-2-methyl-3-oxo-1-phenylpiperazine-2-carboxylate (8p) NPh Cyclization, benzoyl protection, and acylation were accomplished as described in representative procedure 2. Ketopiperazine 8p was isolated by preparative HPLC (Si 2, 20% EtAc in hexanes) as a colorless solid. R f = 0.4 (10% EtAc in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ 7.66 (m, 2H), (m, 1H), 7.40 (app t, J = 7.7 Hz, 2H), (m, 2H), 7.12 (app t, J = 7.4 Hz, 1H), (m, 2H), 5.85 (ddt, J = 17.2, 10.4, 7.0 Hz, 1H), 5.30 (dd, J = 17.2, 1.4 Hz, 1H), 5.25 (dd, J = 10.4, 1.1 Hz, 1H), 4.63 (d, J = 7.0 Hz, 2H), 4.10 (ddd, J = 10.8, 4.7, 2.8 Hz, 1H), (m, 2H), (m, 1H), 1.71 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 173.4, 170.5, 169.7, 147.0, 135.4, 132.0, 131.3, 129.1, 128.3, 128.1, 124.6, 123.8, 119.5, 71.9, 66.5, 46.2, 44.9, 21.7; IR (Neat Film, NaCl) 3061, 3028, 2945, 2903, 2862, 1743, 1693, 1599, 1495, 1450, 1398, 1373, 1283, 1179, 1115, 1075, 961, 865, 842, 811, 724 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 22 H 23 N 2 4 [M+H] + : , found Procedure for the Preparation of Allyl 4-benzoyl-1,2-dimethyl-3- oxopiperazine-2-carboxylate (8q) Et Br SI11 1. ethylene diamine EtH 2. NaEt EtH 90 C, 14 h 1.KHMDS, THF then slow addition of XX 78 C, 1.5 h 2. allyl cyanoformate 78 C, 4 h 1.formaldehyde H/H 2 2. NaCNBH 3 HN N SI13 8q N 1. LDA, THF 78 C, 1.5 h 2. BzCl 78 C, 4 h

22 Supporting Information for Stoltz, et al. SI 21 3,4-Dimethylpiperazin-2-one (SI13) HN N To a solution of ethylene diamine (4.0 ml, 60.0 mmol) in EtH (23 ml) at 0 C was added ethyl 2-bromopropionate (SI11, 3.89 ml, 30.0 mmol) dropwise. The solution was warmed to 23 ºC and allowed to stir overnight open to air. The resulting white solid was removed by filtration, and the filtrate was transferred to a flame-dried flask containing sodium ethoxide (4.49 g, 66.0 mmol). The solution was then heated to 80 C and allowed to stir for 16 hours. The solution was cooled to 23 ºC and concentrated. Half of the material was then taken up in 13.2 ml of H. Formaldehyde (37%, 0.88 ml, 10.0 mmmol) was then added and the mixture was allowed to stir for 12 hours at 23 ºC, at which point NaBH 3 CN (0.77 g, 12.2 mmol) was added and the mixture was allowed to stir overnight open to air. N-methyl ketopiperazine SI13 was isolated as a colorless solid by flash chromatography (Si 2, 5% H in CH 2 Cl 2 to 20% H in CH 2 Cl 2 ). 49% yield. R f = 0.5 (20% H in CH 2 Cl 2 ); 1 H NMR (500 MHz, CDCl 3 ) δ 7.03 (br s, 1H), 3.43 (td, J = 11.0, 10.5, 4.2 Hz, 1H), (m, 1H), 2.87 (dt, J = 12.2, 3.9 Hz, 1H), (m, 1H), 2.51 (ddd, J = 12.1, 10.0, 4.0 Hz, 1H), 2.36 (s, 3H), 1.36 (d, J = 6.8 Hz, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 172.8, 62.6, 50.5, 43.3, 40.7, 15.5; IR (Neat Film, NaCl) 3194, 2986, 2951, 2903, 2846, 2799, 1660, 1495, 1455, 1418, 1354, 1316, 1296, 1249, 1223, 1137, 1097, 1034, 893, 854, 826, 782 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 6 H 13 N 2 [M+H] + : , found Allyl 4-benzoyl-1,2-dimethyl-3-oxopiperazine-2-carboxylate (8q) N Benzoyl protection of and acylation were carried out as described in representative procedure 2. Ketopiperazine 8q was isolated by flash column chromatography (Si 2, 20% EtAc in hexanes) as a colorless oil. R f = 0.5 (40% EtAc in hexanes); 1 H NMR

23 Supporting Information for Stoltz, et al. SI 22 (500 MHz, CDCl 3 ) δ (m, 2H), (m, 1H), (m, 2H), 5.97 (ddt, J = 17.2, 10.4, 6.0 Hz, 1H), 5.40 (dd, J = 17.2, 1.4 Hz, 1H), 5.31 (dd, J = 10.4, 1.1 Hz, 1H), (m, 2H), (m, 2H), 3.28 (ddd, J = 12.7, 8.4, 5.5 Hz, 1H), 2.94 (app dt, J = 12.6, 4.2 Hz, 1H), 2.43 (s, 3H), 1.60 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 174.0, 170.3, 169.0, 135.5, 132.0, 131.6, 128.2, 128.1, 119.7, 71.2, 66.4, 47.3, 44.6, 39.1, 19.5; IR (Neat Film, NaCl) 3062, 2994, 2950, 2900, 2811, 1742, 1691, 1601, 1450, 1398, 1372, 1315, 1275, 1219, 1153, 1109, 1046, 929, 887, 795, 754, 724 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 17 H 20 N 2 4 Na [M+Na] + : , found Procedure for the Preparation of 2-Substituted allyl 4-benzoyl-1-benzyl- 3-oxopiperazine-2-carboxylates 2-thylallyl 4-benzoyl-1-benzyl-3-oxopiperazine-2-carboxylate (10b) LiHMDS (120 mg, 0.61 mmol) was suspended in 1.5 ml of THF and cooled to 78 C. Then ketopiperazine (SI4, 150 mg, 0.51 mmol) dissolved in THF (600 µl) was added dropwise to the LiHMDS solution and allowed to stir at 78 C for 30 minutes, at which point 2-methylallyl 1H-imidazole-1-carboxylate (110 mg, 0.66 mmol) dissolved in 0.5 ml of THF was added dropwise. The reaction mixture was allowed to stir for 6 hours at 78 C at which point full conversion of the starting material was observed by TLC analysis. The reaction mixture was then warmed to 23 ºC and poured into 5 ml of water. The aqueous layer was extracted with EtAc (4 x 10 ml), the combined organics washed with brine (1 x 10 ml), and dried with Na 2 S 4. 2-thylallyl 4-benzoyl-1-benzyl-3- oxopiperazine-2-carboxylate (10b) was isolated as a yellow oil by flash column chromatography (Si 2, 20% EtAc in hexanes). 14% yield. R f = 0.3 (20% EtAc in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), 7.49 (tt, J = 7.1, 1.2 Hz, 1H), (m, 6H), (m, 1H), 5.03 (d, J = 31.1 Hz, 2H), 4.66 (s, 2H), 4.19

24 Supporting Information for Stoltz, et al. SI 23 (s, 1H), 3.94 (ddd, J = 12.6, 8.3, 4.3 Hz, 1H), (m, 2H), 3.76 (ddd, J = 12.6, 5.6, 4.0 Hz, 1H), 3.33 (ddd, J = 12.4, 8.3, 3.9 Hz, 1H), 2.82 (dt, J = 12.4, 4.8 Hz, 1H), 1.78 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 173.8, 167.8, 166.6, 139.2, 136.5, 135.3, 132.2, 129.1, 128.7, 128.4, 128.3, 128.0, 114.5, 69.6, 69.2, 58.7, 44.9, 44.8, 19.8; IR (Neat Film, NaCl) 3062, 3030, 2925, 2853, 1740, 1687, 1600, 1494, 1450, 1402, 1381, 1369, 1282, 1233, 1155, 1074, 1028, 990, 950, 907, 793, 731 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 23 H 25 N 2 4 [M+H] + : , found Chloroallyl 4-benzoyl-1-benzyl-3-oxopiperazine-2-carboxylate (10c) Cl LiHMDS (100 mg, 0.61 mmol) was suspended in 2 ml of THF and cooled to 78 C. Ketopiperazine (SI4, 150 mg, 0.51 mmol) dissolved in THF (2 ml) was then added dropwise and the solution allowed to stir at 78 C for 30 minutes. 2-Chloroallyl 1Himidazole-1-carboxylate (130 mg, 0.66 mmol) dissolved in 1 ml of THF was then added dropwise. The reaction mixture was allowed to stir for 8 hours at 78 C and then warmed to 23 ºC and allowed to stir overnight. The reaction mixture was then poured into 10 ml of water, extracted with EtAc (4 x 15 ml), the combined organics washed with brine (1 x 15 ml), and dried with Na 2 S 4. 2-Chloroallyl 4-benzoyl-1-benzyl-3- oxopiperazine-2-carboxylate (10c) was isolated as a yellow oil by flash column chromatography (Si 2, 10% EtAc in hexanes to 15% EtAc in hexanes). 46% yield. R f = 0.5 (20% EtAc in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), (m, 1H), 7.39 (dd, J = 7.8, 1.4 Hz, 2H), (m, 4H), 7.32 (ttd, J = 8.7, 4.3, 3.7, 2.4 Hz, 1H), 5.54 (dt, J = 2.1, 1.1 Hz, 1H), 5.46 (d, J = 1.9 Hz, 1H), 4.80 (s, 2H), 4.21 (s, 1H), 3.94 (ddd, J = 12.5, 8.2, 4.3 Hz, 1H), (m, 2H), (m, 1H), 3.33 (ddd, J = 12.3, 8.1, 3.9 Hz, 1H), (m, 1H); 13 C NMR (126 MHz, CDCl 3 ) δ 173.7, 167.3, 166.3, 136.3, 135.2, 135.0, 132.3, 129.1, 128.8, 128.4, 128.3, 128.1, 116.5, 69.5, 67.2, 58.8, 44.9, 44.9; IR (Neat Film, NaCl) 3060, 3030, 2949, 2898, 2830, 1744, 1689, 1599, 1491, 1448, 1381, 1280, 1232, 1178, 1138, 1074, 1026, 982, 906, 841, 795,

25 Supporting Information for Stoltz, et al. SI cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 22 H 22 ClN 2 4 [M+H] + : , found Phenylallyl 4-benzoyl-1-benzyl-3-oxopiperazine-2-carboxylate (10d) Ph LiHMDS (140 mg, 0.83 mmol) was suspended in 3 ml of THF and cooled to 78 C. Ketopiperazine (SI4, 200 mg, 0.69 mmol) dissolved in THF (3 ml) was then added dropwise to the LiHMDS solution and allowed to stir at 78 C for 30 minutes. 2- Phenylallyl 1H-imidazole-1-carboxylate (210 mg, 0.90 mmol) dissolved in 1 ml of THF was then added dropwise. The reaction mixture was allowed to stir for 12 hours at 78 C and then warmed to 23 ºC and poured into 10 ml of water. The aqueous layer was extracted with EtAc (4 x 15 ml). The combined organics were washed with brine (1 x 15 ml), and dried with Na 2 S 4. 2-Phenylallyl 4-benzoyl-1-benzyl-3-oxopiperazine-2- carboxylate (10d) was isolated as a yellow oil by flash column chromatography (Si 2, 5% EtAc in hexanes). 21% yield. R f = 0.4 (15% EtAc in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), (m, 3H), (m, 2H), (m, 3H), (m, 3H), (m, 2H), (m, 1H), 5.46 (d, J = 0.9 Hz, 1H), (m, 2H), 4.13 (s, 1H), 3.87 (ddd, J = 12.7, 8.5, 4.4 Hz, 1H), (m, 3H), 3.13 (ddd, J = 12.5, 8.5, 3.9 Hz, 1H), 2.71 (dt, J = 12.2, 4.8 Hz, 1H); 13 C NMR (126 MHz, CDCl 3 ) δ 173.7, 167.8, 166.5, 142.2, 137.9, 136.5, 135.3, 132.1, 129.0, 128.8, 128.6, 128.4, 128.4, 128.3, 127.9, 126.3, 116.9, 69.5, 67.2, 58.4, 44.9, 44.5; IR (Neat Film, NaCl) 3061, 3027, 2925, 2849, 1738, 1688, 1600, 1495, 1450, 1402, 1369, 1281, 1232, 1154, 1074, 1028, 977, 913, 780, 731 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 28 H 27 N 2 4 [M+H] + : , found

26 Supporting Information for Stoltz, et al. SI 25 Representative Procedure for the Asymmetric Decarboxylative Allylic Alkylation of 3-xopiperazine-2-carboxylates, 1,4-Diazepane-2- carboxylates, 1-xooctahydro-9aH-pyrido[1,2-a]pyrazine-9acarboxylates, and 3-xo-1,4-diazaspiro[4.5]decane-2-carboxylates 8b [Pd 2 (pmdba) 3 ] (5 mol%) (S)-(CF 3 ) 3 -t-buphx (12.5 mol %) toluene 40 C, 14 h 9b (S)-3-Allyl-1-benzoyl-4-benzyl-3-methylpiperazin-2-one (9b) In a nitrogen-filled glovebox, an oven-dried 20 ml scintillation vial was charged with [Pd 2 (pmdba) 3 ] (27.4 mg, mmol, 0.05 equiv) or [Pd 2 (dba) 3 ] (22.9 mg, mmol, 0.05 equiv), (S)-(CF 3 ) 3 -t-buphx (37.0 mg, mmol, equiv), toluene (15 ml or 13 ml if the substrate is an oil), and a magnetic stir bar. The vial was stirred at ambient glovebox temperature (~28 C) for 30 min and then the substrate (8b, 182 mg, 0.50 mmol) was added either as a solid or as a solution in toluene (2 ml). The vial thus charged was sealed and heated to 40 C. When complete consumption of the starting material was observed by thin layer chromatography, the reaction mixture was removed from the glovebox, concentrated under reduced pressure, and purified by flash chromatography to afford the desired alkylated product. Ketopiperazine 9b was isolated as a yellow oil by flash column chromatography (Si 2, 10% Et 2 and 0.2% 2 NEt in hexanes). 89% yield. R f = 0.4 (10% EtAc in hexanes, two developments); 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), (m, 1H), (m, 6H), 7.29 (t, J = 7.2 Hz, 1H), 6.06 (ddt, J = 17.1, 10.3, 7.2 Hz, 1H), (m, 2H), 4.02 (d, J = 13.6 Hz, 1H), 3.87 (d, J = 12.2 Hz, 1H), 3.60 (td, J = 11.9, 4.0 Hz, 1H), 3.43 (d, J = 13.3 Hz,

27 Supporting Information for Stoltz, et al. SI 26 1H), (m, 3H), 2.64 (dd, J = 14.9, 6.5 Hz, 1H), 1.45 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 175.0, 174.3, 138.9, 136.3, 134.0, 131.6, 128.7, 128.2, 127.8, 127.5, 118.1, 67.3, 53.0, 45.1, 42.2, 41.5, 18.7; IR (Neat Film, NaCl) 3063, 3029, 2974, 2827, 1701, 1684, 1601, 1494, 1449, 1378, 1363, 1317, 1286, 1223, 1152, 1134, 1027, 993, 912, 794, 724 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 22 H 25 N 2 2 [M+H] + : , found ; [α] 25.0 D 58.4 (c 0.97, H, 91% ee). (S)-(2-Allyl-2-methyl-3-oxopiperazine-1,4-diyl)bis(phenylmethanone) (9a) NBz Ketopiperazine 9a was isolated as an off-white foam by flash column chromatography (Si 2, 15% EtAc in hexanes to 25% EtAc in hexanes). 89% yield. R f = 0.4 (35% EtAc in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), (m, 1H), (m, 7H), 5.85 (dddd, J = 17.0, 10.1, 8.7, 6.2 Hz, 1H), 5.24 (ddt, J = 17.0, 2.3, 1.2 Hz, 1H), 5.20 (dd, J = 10.1, 2.1 Hz, 1H), 4.14 (ddd, J = 13.1, 5.8, 2.9 Hz, 1H), 3.79 (ddd, J = 13.1, 8.9, 2.9 Hz, 1H), 3.71 (ddd, J = 14.2, 5.8, 2.9 Hz, 1H), 3.60 (dd, J = 13.9, 8.7 Hz, 1H), 3.53 (ddd, J = 14.2, 8.9, 2.9 Hz, 1H), 2.88 (ddt, J = 13.9, 6.2, 1.2 Hz, 1H), 2.00 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 173.9, 172.5, 171.2, 137.0, 135.6, 133.0, 131.9, 130.2, 128.9, 128.3, 127.6, 126.7, 119.9, 68.4, 46.6, 44.2, 39.4, 24.3; IR (Neat Film, NaCl) 3057, 2978, 2934, 1685, 1643, 1600, 1448, 1405, 1364, 1286, 1210, 1149, 1075, 990, 934, 828, 788, 716 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 22 H 23 N 2 3 [M+H] + : , found ; [α] 25.0 D 15.8 (c 0.78, H, 52% ee). (S)-3-Allyl-1-benzoyl-4-(4-methoxybenzyl)-3-methylpiperazin-2-one (9c) NPMB

28 Supporting Information for Stoltz, et al. SI 27 Ketopiperazine 9c was isolated as a yellow oil by flash column chromatography (Si 2, 10% EtAc in hexanes). 85% yield. R f = 0.4 (20% EtAc in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ 7.55 (dt, J = 8.4, 1.6 Hz, 2H), (m, 1H), (m, 2H), 7.30 (d, J = 8.6 Hz, 2H), (m, 2H), 6.05 (ddt, J = 17.1, 10.3, 6.9 Hz, 1H), (m, 2H), 3.94 (d, J = 13.4 Hz, 1H), 3.85 (dt, J = 12.3, 3.4 Hz, 1H), 3.82 (s, 3H), 3.55 (ddd, J = 12.2, 10.7, 4.3 Hz, 1H), 3.34 (d, J = 13.4 Hz, 1H), 2.88 (dt, J = 12.7, 3.8 Hz, 1H), (m, 2H), 2.63 (dd, J = 14.9, 6.6 Hz, 1H), 1.43 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 175.2, 174.4, 159.0, 136.3, 134.1, 131.5, 130.8, 129.7, 128.2, 127.7, 118.0, 114.0, 67.2, 55.4, 52.3, 45.2, 41.9, 41.4, 18.6; IR (Neat Film, NaCl) 2938, 2834, 1683, 1611, 1512, 1449, 1377, 1317, 1287, 1245, 1224, 1177, 1153, 1133, 1034, 910, 822 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for C 23 H 27 N 2 3 [M+H] + : , found ; [α] 25.0 D 75.0 (c 0.86, CHCl 3, 90% ee). (S)-3-Allyl-4-benzyl-1-(4-fluorobenzoyl)-3-methylpiperazin-2-one (9d) F N Ketopiperazine 9d was isolated as a yellow oil by flash column chromatography (Si 2, 5% EtAc in hexanes to 10% EtAc in hexanes). 86% yield. R f = 0.5 (15% EtAc in hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ 7.59 (dd, J = 8.1, 5.7 Hz, 2H), 7.40 (d, J = 7.5 Hz, 2H), 7.35 (t, J = 7.4 Hz, 2H), 7.29 (t, J = 7.0 Hz, 1H), 7.06 (t, J = 8.5 Hz, 2H), 6.08 (ddt, J = 17.2, 9.9, 6.9 Hz, 1H), 5.17 (t, J = 13.8 Hz, 2H), 4.02 (d, J = 13.7 Hz, 1H), 3.85 (dt, J = 12.1, 3.1 Hz, 1H), 3.57 (td, J = 11.4, 4.2 Hz, 1H), 3.41 (d, J = 13.7 Hz, 1H), 2.89 (dt, J = 12.7, 3.6 Hz, 1H), 2.80 (tt, J = 11.0, 5.1 Hz, 2H), (m, 1H), 1.44 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 175.2, 173.2, (d, 1 J CF = Hz), 138.9, 134.0, (d, 4 J CF = 3.3 Hz), (d, 3 J CF = 9.0 Hz), 128.7, 128.6, 127.5, 118.1, (d, 2 J CF = 22.1 Hz), 67.3, 53.0, 45.3, 42.2, 41.5, 18.7; IR (Neat Film, NaCl) 3065, 3027, 2976, 2942, 2828, 1681, 1602, 1507, 1453, 1408, 1378, 1318, 1285, 1226, 1152, 1134, 1098, 1028, 994, 913, 843, 769, 738 cm 1 ; HRMS (MM: ESI-APCI) m/z calc'd for